DESCRIPTION (applicant's abstract): Reproductive behaviors, especially lordosis, have proven excellent subjects for brain/behavior analyses. Now, for discerning genetic influences on animal behavior, female mice will be ideal. Here we propose to study two genes: (a) for oxytocin (OT), and (b) for its receptor (OTR). This is an exciting system, involved not only in reproductive and parental behaviors but also in the more general process of affiliation. As an important integrative neuropeptide, OT coordinates certain natural behaviors with their corresponding autonomic preparations. OT neurons, important for lordosis, are strategically convenient, located in discrete magnocellular hypothalamic groups. How do these two genes influence reproductive behaviors? I. At the molecular/biochemical level, we will use G-protein analyses including newly available specific-G-protein knockout mice as well as antisense DNA techniques, OTR antagonists and OTR knockout mice to test the hypothesis that OT, operating through the OTR, activates specific G-proteins, thus to increase ventromedial hypothalamic neuronal electrical activity, thus to drive lordosis behavior. II. At the behavioral level, we will use OT knockout mice, newly available OTR antagonists and antisense DNA approaches together with assays not only of reproductive behaviors but also of responses to stress and anxiety, to explore the hypothesis that these two genes are not limited to direct effects on lordosis. They calm the female mouse and protect reproductive behaviors from disruption under mildly stressful conditions. Novel "mouse burrow systems" will be included in our assays. As part of the project we will address two "puzzles": (i) the astonishingly weak phenotype reported so far from OT knockouts: How could the OT knockout mouse have such a restricted phenotype in view of the peptide's strong physiological and behavioral roles? (ii) The impressive behavioral differences between OT and vasopressin in the face of their chemical similarities: Where can we dissociate OT mechanisms from vasopressin's in a manner to help explain their behavioral differences? Overall, this proposal continues a "multilevel" investigation which exploits the specificity of the genetic code in order to analyze natural behavioral mechanisms.